Human skin (~2 m²) is composed of several distinct layers which house different physiological systems and subsequent functions. The epidermis, the most superficial layer of the skin, can be subdivided into five layers based upon keratinocytes differentiation: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale [2]. The outermost layer, stratum corneum, is the principal barrier layer, consisting of a complex arrangement of terminally differentiated keratinocytes, defined as corneocytes, embedded in a peculiar lipid matrix mainly composed of cholesterol, fatty acid, and ceramides [2]. This complex structure, first described as a “brick and mortar system”, creates a tortuous pathway and barrier for cutaneous stressors [3,4]. These layers represent the first line of defense against physical trauma, microorganisms, and environmental stressors such as ultraviolet radiation, particulate matter, and ozone [5]. The second layer of the skin, the dermis, is directly connected to the epidermis and can be segmented into two layers. The papillary layer, stratum papillare, connects the dermis to the epidermis and consists of thin collagen fibers; the reticular layer, stratum reticulare, is the deepest layer of the dermis and is composed of dense collagen fibers [6,7]. The dermis is composed of numerous cellular components: principally fibroblasts, along with macrophages, T and B cells, mast cells, blood vessels, lymphatics, and nerves [5,7]. The hypodermis, also known as the subcutaneous layer, is the final layer of the skin, which is composed of adipose tissue. This thick lipid layer is particularly useful in its ability to act as a barrier, store water, and absorb various lipophilic compounds [2,6]. The skin is vital for protection, thermoregulation, sensation, water storage, absorption, expression, and synthesis of vitamin D₃ [8].

Aside from the lipid matrix barrier, the skin is equipped with several enzymatic and non-enzymatic defensive mechanisms. Endogenous defensive enzymes prevent a harmful accumulation of ROS such as the superoxide anion (O₂^•−), hydroxyl radical (OH^•), alkoxy radical (RO^•), and peroxyl radical (ROO^•) [9]. Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) are three enzymes present in the skin which are responsible for preventing cutaneous oxidative damage [10]. This physiological mechanism can handle moderate levels of ROS; however, exposure to environmental pollutants can result in an excessive and chronic increase in ROS which overwhelms the antioxidant defenses of the skin [5,11]. Levels of these endogenous antioxidant enzymes vary between the epidermis and the dermis, with a higher concentration in the epidermis than dermis [5].

In addition to this enzymatic system, numerous nonenzymatic antioxidant micronutrients also help to prevent oxidative damage. L-ascorbic acid (vitamin C), ɑ-tocopherol (vitamin E), glutathione (GSH), uric acid, and ubiquinol are among the most predominant cutaneous antioxidants [12]. Vitamin E is a lipid-soluble antioxidant that protects the skin by preventing lipid peroxidation [13]. Furthermore, increased levels of vitamin E have been shown to inhibit prostaglandin E2 (PGE2) expression, a key mediator of inflammation linked to skin aging [13,14]. In addition to vitamin E, vitamin C also plays a key protective role [5,15,16]. Of note, the epidermis houses more of these antioxidants than the dermis in a gradient fashion, with the highest levels in the epidermis deeper layers and the lower levels in the stratum corneum [12].

Ultraviolet light (UV) exposure is necessary for our body to produce vitamin D₃. However, prolonged exposure can result in a cascade of harmful cutaneous effects [17]. UV light represents wavelengths of 400 nm to 100 nm and can be divided into UVA and UVB. UVA radiation consists of 400–314 nm wavelengths and represents more than 95% of UV light which passes through earth’s protective stratospheric ozone layer. UVB radiation is highly mutagenic and cytotoxic to cutaneous systems; however, it is usually absorbed efficiently by the ozone layer [18]. UV light absorption causes the photochemical generation of ROS, which leads to a cascade of damaging processes in cutaneous structures [19]. While ROS are naturally produced in skin cell mitochondria during normal oxidative metabolism, the continued production from exogenous stressors such as UV light, pollution (including ozone, particulate matters, etc.), and cigarette smoke can overwhelm antioxidant defenses, resulting in oxidative damage and contributing to skin extrinsic premature aging [20,21]. Indeed, as previously mentioned, although the skin is well equipped with enzymatic and non-enzymatic defensive systems, the continued chronic exposure to outdoor insults can overcome the cutaneous physiological protection and lead to skin damage [22].

Tropospheric ground level ozone (O₃) is the result of photochemical reactions between nitrogen oxides, volatile organic compounds, and carbon monoxide [23]. The sources of these compounds are pollutants emitted from power plants, cars, and chemical plants. In the United States, over 100 million people reside in areas that exceed the health-based National Ambient Air Quality Standard (NAAQS) of 70 parts per billion (ppb) for O₃ [24]. This statistic becomes more daunting when using the World Health Organization (WHO) O₃ standards, which are set at 50 ppb [25]. Daily exposure to high concentrations of O₃ has been associated with higher incidence of respiratory and cardiorespiratory mortality, especially in those with preexisting chronic conditions such as asthma [26]. Unlike UV light, O₃ is unable to penetrate the cutaneous tissues, and its effect is mainly mediated by a cascade of bioactive reactions, leading to increased lipid peroxidation and ROS formation [27] which modulate key physiological inflammatory pathways and exhaust cutaneous antioxidants, causing adverse skin conditions [28,29]. Indeed, although ozone cannot penetrate skin, it can initiate free radical reactions by interacting with biomolecules present within the outermost layer of the skin, stratum corneum (SC), including lipids, proteins, and DNA, leading to the production hydrogen peroxide (H₂O₂) and nonradical species, such as aldehydes [30]. O₃ secondary mediators can further perpetuate the damage throughout the skin by interacting with keratinocytes and fibroblasts, inducing oxidative stress reactions and lipid peroxidation [31].

Particulate matter (PM) is air pollution that is a mixture of solid and liquid particles of varying sizes. These particles can contain acids, organic chemicals, metals, soils, or dust particles and are categorized by diameter (µM): PM₁₀, PM_2.5, and PM_0.1. Sources of PM include natural origins such as volcanoes, dust storms, and forest fires; industries contribute to PM levels through processing, burning of fossil fuels, and industrial waste products. Epidemiological studies have associated 8.9 million deaths in 2015 with long-term exposure to fine PM [32]. Fine–ultrafine PM_0.1–2.5 is most directly responsible for skin barrier dysfunction and the exacerbation of skin ailments such as atopic dermatitis, due to their ability to circumvent physiological barriers [33]. The mechanisms involved in PM-associated skin disorders result from increased oxidative damage due to PM interaction with the skin cells. Although still under debate, it has been suggested that PMs can move through the skin through hair follicles or transdermally, generating a cascade of biological oxidative damage stress. PAHs are components of UFPs that can be absorbed through the skin and eventually damage the mitochondria, resulting in intracellular ROS production. These damaged mitochondria produce superoxide anions, which can be converted into H₂O₂ that can then undergo the Fenton reaction to produce hydroxyl radicals, resulting in increased ROS and activation of redox sensitive transcription factors, such as AP1 and NFκB. In addition, interactions between PM particles and surfaces can result in extracellular ROS production, again resulting in the activation of redox-sensitive transcription factors AP1 and NFκB. The consequences of oxidative stress result in antioxidant depletion, lipid peroxidation, and DNA damage. In support of this idea, our lab has demonstrated that exposure to PM particles induces nuclear translocation of NFκB, increases levels of HNE, and promotes DNA damage in ex vivo human biopsies [34,35].

Blueberries contain an abundance of bioactive compounds such as flavonoids and other polyphenolic compounds, which have strong antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, and other health-relevant properties [36]. The polyphenolic composition of blueberries is influenced by several factors such as variety, season, method of cultivation, and growing location [37]. Anthocyanins are one of the predominant polyphenols present in blueberries which are responsible for their blue color; additionally, they are also one of the most powerful natural antioxidants [38]. In vitro studies exhibit anthocyanin’s significant antioxidative ability to scavenge ROS and have beneficial biological functions such as enzyme inhibition, as well as anti-inflammatory and antibacterial effects [39,40]. Consistent consumption of blueberries has been proven to increase total anthocyanin-derived metabolites in blood serum [41]. While anthocyanins are the dominant form of polyphenol in blueberries, they also contain many other phenolic compounds such as flavonols, ellagitannins, proanthocyanidins, hydroxycinnamic acids, gallotannins, and hydroxybenzoic acids [42]. Polyphenols undergo significant modification through the digestive process as they are metabolized; microbes biotransform polyphenols through deglycosylation, dihydroxylation, demethylation, decarboxylation, and isomerization, creating a variety of low molecular weight analytes which are either intermediates or products of metabolism. When the three phases of polyphenol digestion (salivary, gastric, and intestinal) are complete, 169 polyphenolic metabolites can be found in measurable amounts in blood plasma [42]. Among the 169 serum polyphenol metabolites, 58 blueberry-derived metabolites significantly change in concentration following blueberry consumption [42]. Table 1 exhibits the top five metabolites upregulated in blood plasma following the consumption of a blueberry beverage. While many question the ability of polyphenols to demonstrate antioxidant action in vivo because of their apparent poor bioavailability, the current literature suggests that the consumption of polyphenol-rich blueberries protects against gastrointestinal problems, cancers, diabetes, and cardiovascular and neurodegenerative diseases through their phenolic metabolites after catabolism by the gut microbiome [43,44]. Furthermore, prebiotic efficiency of parent blueberry polyphenols such as anthocyanins can be maximized through microencapsulation, consequently thwarting degradation from the upper gastrointestinal tract [45]. The health benefits of blueberries are not limited to bioactive polyphenols; a typical serving of blueberries contains large amounts of vitamin C and E, among the major antioxidants in cutaneous systems [46]. Blueberries are also rich in retinol and vitamin A, which have known beneficial effects in the skin [46,47].